KCNH2 Variant E37A Detail

We estimate the penetrance of LQTS for KCNH2 E37A is 44%. We are unaware of any observations of this variant in individuals. E37A is not present in gnomAD. E37A has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E37A around 44% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.799 0.0 -2 0.458 47
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance density is our previously published method to calculate the average LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT2 Other Disease
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 6 4 -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

E37A has 29 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. NOTE: some residues appear multiple times at different distances since the functional KV11.1 channel (protein product of KCNH2/hERG) is a homotetramer and occasionally the same residue from multiple subunits is present within the 15A window. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
37 0
38 5
36 5 V36X,
35 7 R35W,
39 7 C39R, C39X,
34 9 A34T,
40 9
33 10 N33T,
63 11 P63H,
794 11 V794D, V794I,
791 11 R791W, R791Q,
796 12 V796Del, V796L, V796L,
61 12 Q61R,
64 12 C64R, C64Y,
32 12 A32T,
41 13 V41A,
792 13
795 13 V795I,
62 13 R62Q,
86 13 L86R,
87 14 L87P,
65 14 T65P,
125 14
42 14 I42N,
123 14
124 14 M124R, M124T,
122 15
793 15 D793N,
819 15 N819K, N819K,